Fatigue is one of the most frequently reported symptoms in patients with cancer and can profoundly affect a cancer patient's quality of life, treatment adherence, and health care utilization. Both pre- and post-treatment fatigue is also prognostic for pathologic tumor response and poor survival. Patients with head and neck cancer, who typically receive chemo radiotherapy (chemoRT), have high rates of fatigue, compared to patients with other types of cancer. This fatigue can persist or worsen up to one-year post-treatment. Recent research on Intensity-modulated RT (IMRT), a new radiotherapy that targets tumors with higher doses of radiation while avoiding normal structures, has shown that head and neck cancer patients receiving IMRT experience even higher fatigue compared to conventional-RT. Currently, there is no Food and Drug Administration (FDA)- approved pharmacological agent that effectively prevents or treats fatigue. Understanding the molecular mechanisms of fatigue is critical to its successful management and the development of targeted therapies. Recent studies by our group and others, have found that fatigued cancer patients exhibit higher peripheral blood inflammatory markers, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha, than those without fatigue. Interestingly, this inflammation has been found months to years after treatment and remains associated with increased fatigue in cancer survivors. This phenomenon raises a very important and clinically-relevant question: How can inflammation and its association with fatigue last for months to years after cancer treatment? A growing body of evidence suggests a critical role for epigenetic changes in human pathologies including inflammation and behavioral disorders, and demonstrates the importance of epigenetic modifications in the prediction and treatment of symptoms/diseases. Therefore, one potential explanation of persisting inflammation and fatigue is that cancer and its treatment with chemoIMRT leads to long-lasting epigenetic changes. In this application, we propose to examine 1) whether epigenetic changes are associated with inflammation and fatigue during the acute phase of chemoIMRT and 2) whether epigenetic changes seen acutely following treatment persist long after chemoIMRT and are associated with inflammation and fatigue. This will be a longitudinal, observational study following patients from pre- to up to one year post chemoIMRT. We will leverage half of our data from a parent study (K99NR014587; PI Xiao) that is prospectively enrolling head and neck cancer patients testing the association between fatigue and inflammation. We will assemble a cohort from the parent study and the proposed study of only those patients receiving concurrent chemoIMRT. The findings may indicate new epigenetic biomarkers for fatigued patients and novel behavioral and/or pharmacologic targets for the epigenetic therapy of fatigue. A stellar multidisciplinary research team with extensive expertise in epigenetics, genomics, inflammation/ immunology, and head and neck cancer treatment and symptoms has been built to assure the successful completion of this proposed study.